Viral fitness and antigenic determinants of porcine parvovirus at the amino acid level of the capsid protein

2021 ◽  
Author(s):  
André Felipe Streck ◽  
Cláudio Wageck Canal ◽  
Uwe Truyen
Keyword(s):  
Amino Acid ◽  
Capsid Protein ◽  
Immune Escape ◽  
Amino Acid Level ◽  
Binding Activity ◽  
Viral Fitness ◽  
Antigenic Determinants ◽  
Amino Acid Substitutions ◽  
Porcine Parvovirus ◽  
Predominant Factor

Since 2001, strains of porcine parvovirus (PPV), designated 27a -like strains, were observed in Europe, suggesting a predominance of these viruses over older strains. The reasons for the obvious evolutionary advantage are unknown. Here, a series of mutants containing amino acid replacements found in the predominant field strains were generated in a PPV-NADL2 background and their impact on replication efficiency and antibody binding activity was determined. Some amino acid substitutions observed in the 27a- like strains significantly increased viral fitness and decreased neutralization activity of sera raised against commercial vaccines and old virus strains (e.g. NADL2). These mutant viruses and a monoclonal antibody raised against a classical PPV strain defined an 27a-specific neutralizing epitope around amino acid 228 of the capsid protein VP2. Based on the analysis of the mutant viruses, it is hypothesized that the predominant factor for the global spread of the PPV-27a strain substitutions is an increased viral fitness of the 27a- like viruses, possibly supported by a partial immune selection. This is reminiscent to the evolution of canine parvovirus and worldwide replacement of the original virus by the so-called new antigenic types. Importance Porcine parvovirus is one of the most important causes of reproductive failure in swine. Recently, despite the continuous use of vaccines, “new” strains emerged, leading to the hypothesis that the emergence of new amino acid substitutions could be a viral adaptation to the immune response against the commercial vaccines. Our results indicate the amino acid substitutions observed in the 27a -like strains can modify viral fitness and antigenicity. However, an absolute immune escape was not evident.

scholarly journals S-Acylation of Proteins of Coronavirus and Influenza Virus: Conservation of Acylation Sites in Animal Viruses and DHHC Acyltransferases in Their Animal Reservoirs

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 669
Author(s):  
Dina A. Abdulrahman ◽  
Xiaorong Meng ◽  
Michael Veit
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Ion Channels ◽  
Substrate Specificity ◽  
Influenza A ◽  
3D Structure ◽  
Viral Fitness ◽  
Amino Acid Substitutions ◽  
Essential Function ◽  
Animal Reservoirs

Recent pandemics of zoonotic origin were caused by members of coronavirus (CoV) and influenza A (Flu A) viruses. Their glycoproteins (S in CoV, HA in Flu A) and ion channels (E in CoV, M2 in Flu A) are S-acylated. We show that viruses of all genera and from all hosts contain clusters of acylated cysteines in HA, S and E, consistent with the essential function of the modification. In contrast, some Flu viruses lost the acylated cysteine in M2 during evolution, suggesting that it does not affect viral fitness. Members of the DHHC family catalyze palmitoylation. Twenty-three DHHCs exist in humans, but the number varies between vertebrates. SARS-CoV-2 and Flu A proteins are acylated by an overlapping set of DHHCs in human cells. We show that these DHHC genes also exist in other virus hosts. Localization of amino acid substitutions in the 3D structure of DHHCs provided no evidence that their activity or substrate specificity is disturbed. We speculate that newly emerged CoVs or Flu viruses also depend on S-acylation for replication and will use the human DHHCs for that purpose. This feature makes these DHHCs attractive targets for pan-antiviral drugs.

scholarly journals Mechanism of Darunavir (DRV)’s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Manabu Aoki ◽  
Debananda Das ◽  
Hironori Hayashi ◽  
Hiromi Aoki-Ogata ◽  
Yuki Takamatsu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Critical Role ◽  
Viral Fitness ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Genetic Barrier ◽  
High Level ◽  
Hiv 1

ABSTRACTDarunavir (DRV) has bimodal activity against HIV-1 protease, enzymatic inhibition and protease dimerization inhibition, and has an extremely high genetic barrier against development of drug resistance. We previously generated a highly DRV-resistant HIV-1 variant (HIVDRVRP51). We also reported that four amino acid substitutions (V32I, L33F, I54M, and I84V) identified in the protease of HIVDRVRP51are largely responsible for its high-level resistance to DRV. Here, we attempted to elucidate the role of each of the four amino acid substitutions in the development of DRV resistance. We found that V32I is a key substitution, which rarely occurs, but once it occurs, it predisposes HIV-1 to develop high-level DRV resistance. When two infectious recombinant HIV-1 clones carrying I54M and I84V (rHIVI54Mand rHIVI84V, respectively) were selected in the presence of DRV, V32I emerged, and the virus rapidly developed high-level DRV resistance. rHIVV32Ialso developed high-level DRV resistance. However, wild-type HIVNL4-3(rHIVWT) failed to acquire V32I and did not develop DRV resistance. Compared to rHIVWT, rHIVV32Iwas highly susceptible to DRV and had significantly reduced fitness, explaining why V32I did not emerge upon selection of rHIVWTwith DRV. When the only substitution is at residue 32, structural analysis revealed much stronger van der Waals interactions between DRV and I-32 than between DRV and V-32. These results suggest that V32I is a critical amino acid substitution in multiple pathways toward HIV-1’s DRV resistance development and elucidate, at least in part, a mechanism of DRV’s high genetic barrier to development of drug resistance. The results also show that attention should be paid to the initiation or continuation of DRV-containing regimens in people with HIV-1 containing the V32I substitution.IMPORTANCEDarunavir (DRV) is the only protease inhibitor (PI) recommended as a first-line therapeutic and represents the most widely used PI for treating HIV-1-infected individuals. DRV possesses a high genetic barrier to development of HIV-1’s drug resistance. However, the mechanism(s) of the DRV’s high genetic barrier remains unclear. Here, we show that the preexistence of certain single amino acid substitutions such as V32I, I54M, A71V, and I84V in HIV-1 protease facilitates the development of high-level DRV resistance. Interestingly, allin vitro-selected highly DRV-resistant HIV-1 variants acquired V32I but never emerged in wild-type HIV (HIVWT), and V32I itself rendered HIV-1 more sensitive to DRV and reduced viral fitness compared to HIVWT, strongly suggesting that the emergence of V32I plays a critical role in the development of HIV-1’s resistance to DRV. Our results would be of benefit in the treatment of HIV-1-infected patients receiving DRV-containing regimens.

scholarly journals Antigenic Determinants of Possible Vaccine Escape by Porcine Circovirus Subtype 2b Viruses

2015 ◽  
Vol 9s2 ◽  
pp. BBI.S30226 ◽  
Author(s):  
Megan Constans ◽  
Marvin Ssemadaali ◽  
Oleksandr Kolyvushko ◽  
Sheela Ramamoorthy
Keyword(s):  
T Cell ◽  
B Cell ◽  
Capsid Protein ◽  
Rational Design ◽  
Immune Escape ◽  
Clinical Signs ◽  
Porcine Circovirus ◽  
Antigenic Determinants ◽  
B Cell Epitopes ◽  
Cell Functions

Currently available commercial vaccines against porcine circovirus strain 2 (PCV2) solely target the PCV2a genotype. While PCV2 vaccines are highly effective in preventing clinical signs, PCV2b has dominated over the PCV2a genotype in prevalence, corresponding with the introduction of PCV2a vaccines. A recently emerged PCV2b recombinant with an additional amino acid in the capsid protein, designated the mutant PCV2b (mPCV2b), is cause for concern due to its increased virulence and rapid spread. The accumulation of recent evidence for the increased genetic diversity in PCV2 suggests that current vaccines against PCV2a may be inducing selection pressure and driving viral evolution. In this study, the hypothesis that differences in key immune epitopes between the PCV2a vaccine strains, a classical PCV2b strain called PCV2b 41513 obtained from a vaccine-failure case, and mPCV2b strains could promote vaccine escape was tested using immuno-informatic tools. In the major viral proteins, 9 of the 18 predicted swine leukocyte antigens (SLA) class-I epitopes, 8 of the 22 predicted SLA class-II epitopes, and 7 of the 25 predicted B cell epitopes varied between the vaccine and field strains. A majority of the substitutions in both the T- and B-cell epitopes were located in the capsid protein. Some B- and T-cell epitopes that were identified as immunogenic in the vaccine strain were not identified as epitopes in the field strains, indicating a subtle shift in the antigenic profile of the field strains. Several nonconserved epitopes had both predicted B- and T-cell functions. Therefore, substitutions in the dual epitopes could affect both arms of the immune response simultaneously, causing immune escape. Our findings support further rational design of PCV2 vaccines to increase the current threshold of protection.

scholarly journals Evolutionary Analyses of RNA Editing and Amino Acid Recoding in Cephalopods

2019 ◽  
Author(s):  
Mingye (Christina) Wang ◽  
Erik Mohlhenrich
Keyword(s):  
Amino Acid ◽  
Candidate Genes ◽  
Rna Editing ◽  
Amino Acid Level ◽  
Nucleotide Composition ◽  
Model Organisms ◽  
Future Research ◽  
Amino Acid Substitutions ◽  
Behavioral Complexity ◽  
Fitness Advantage

AbstractRNA editing is a post-transcriptional modification process that alters nucleotides of mRNA and consequently the amino acids of the translated protein without changing the original DNA sequence. In human and other mammals, amino acid recoding from RNA editing is rare, and most edits are non-adaptive and provide no fitness advantage (1). However, recently it was discovered that in soft-bodied cephalopods, which are exceptionally intelligent and include squid, octopus, and cuttlefish, RNA editing is widespread and positively selected (2). To examine the effects of RNA editing on individual genes, we developed a “diversity score” system that quantitatively assesses the amount of diversity generated in each gene, incorporating combinatorial diversity and the radicalness of amino acid changes. Using this metric, we compiled a list of top 100 genes across the cephalopod species that are most diversified by RNA editing. This list of candidate genes provides directions for future research into the specific functional impact of RNA editing in terms of protein structure and cellular function on individual proteins. Additionally, considering the connection of RNA editing to the nervous system, and the exceptional intelligence of cephalopod, the candidate genes may shed light to the molecular development of behavioral complexity and intelligence. To further investigate global influences of RNA editing on the transcriptome, we investigated changes in nucleotide composition and codon usage biases in edited genes and coleoid transcriptome in general. Results show that these features indeed correlate with editing and may correspond to causes or effects of RNA editing. In addition, we characterized the unusual RNA editing in cephalopods by analyzing ratio of radical to conservative amino acid substitutions (R/C) and distribution of amino acid recoding from editing. Our results show that compared to model organisms, editing in cephalopods have significantly decreased R/C ratio and distinct distribution of amino acid substitutions that favor conservative over radical changes, indicating selection at the amino acid level and providing a potential mechanism for the evolution of widespread RNA editing in cephalopods.

scholarly journals Nucleotide Polymorphism and Natural Selection at the Pantophysin (Pan I) Locus in the Atlantic Cod, Gadus morhua (L.)

Genetics ◽  
2001 ◽  
Vol 157 (1) ◽  
pp. 317-330 ◽  
Author(s):  
Grant H Pogson
Keyword(s):  
Natural Selection ◽  
Amino Acid ◽  
Gadus Morhua ◽  
Atlantic Cod ◽  
Amino Acid Level ◽  
Amino Acid Substitutions ◽  
Significant Heterogeneity ◽  
Nucleotide Sequence Variation ◽  
Spatially Varying ◽  
Spatially Varying Selection

Abstract Molecular studies of nucleotide sequence variation have rarely attempted to test hypotheses related to geographically varying patterns of natural selection. The present study tested the role of spatially varying selection in producing significant linkage disequilibrium and large differences in the frequencies of two common alleles at the pantophysin (Pan I) locus among five populations of the Atlantic cod, Gadus morhua. Nucleotide sequences of 124 Pan I alleles showed strong evidence for an unusual mix of balancing and directional selection but no evidence of stable geographically varying selection. The alleles were highly divergent at both the nucleotide level (differing on average by 19 mutations) and at amino acid level (each having experienced three amino acid substitutions since diverging from a common ancestral allele). All six amino acid substitutions occurred in a 56-residue intravesicular loop (IV1 domain) of the vesicle protein and each involved a radical change. An analysis of molecular variation revealed significant heterogeneity in the frequencies of recently derived mutations segregating within both allelic classes, suggesting that two selective sweeps may be presently occurring among populations. The dynamic nature of the Pan I polymorphism in G. morhua and clear departure from equilibrium conditions invalidate a simple model of spatially varying selection.

scholarly journals The Molecular Determinants of Antigenic Drift in a Novel Avian Influenza A (H9N2) Variant Virus

2021 ◽  
Author(s):  
Yiqing Zheng ◽  
Yanna Guo ◽  
Yingfei Li ◽  
Bing Liang ◽  
Xiaoyuan Sun ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Avian Influenza ◽  
Vaccine Strain ◽  
Influenza A ◽  
Immune Escape ◽  
Antigenic Drift ◽  
Amino Acid Substitutions ◽  
Variant Virus ◽  
Molecular Determinants

Abstract Background: In early 2020, a novel H9N2 AIV immune escape variant emerged in South China and rapidly spread throughout mainland China. The effectiveness of the current H9N2 vaccine is being challenged by emerging immune escape strains. Assessing key amino acid substitutions that contribute to antigenic drift and immune escape in the HA gene of circulating strains is critical for understanding virus evolution and in selecting more effective vaccine components. Methods: In this study, a representative immune escape strain, A/chicken/Fujian/11/2020 (FJ/20), differed from current H9N2 vaccine strain, A/chicken/Anhui/LH99/2017 (AH/17) by 18 amino acids in the head domain. To investigate the molecular determinants of antigenic drift of FJ/20, a panel of mutants were generated by reverse genetics including specific amino acids changes in the HA genes of FJ/20 and AH/17. The antigenic effect of the substitutions was evaluated by hemagglutination inhibition (HI) assay and antigenic cartography. Results: Fujian-like H9N2 viruses had changed antigenicity significantly, having mutated into an antigenically distinct sub-clade. Relative to the titers of the vaccine virus AH/17, the escape strain FJ/20 saw a 16-fold reduction in HI titer against antiserum elicited by AH/17. Our results showed that seven residue substitutions (D127S, G135D, N145T, R146Q, D179T, R182T and T183N) near the HA receptor binding sites were critical for converting the antigenicity of both AH/17 and FJ/20. Especially, the combined mutations 127D, 135G, 145N, and 146R could be a major factor of antigenic drift in the current immune escape variant FJ/20. The avian influenza A (H9N2) variant virus need further ongoing epidemiological surveillance.Conclusions: In this study, we evaluated the relative contributions of different combinations of amino acid substitutions in the HA globular head domain of the immune escape strain FJ/20 and the vaccine strain AH/17. Our study provides more insights into the molecular mechanism of the antigenic drift of the H9N2 AIV immune escape strain. This work identified important markers for understanding H9N2 AIV evolution as well as for improving vaccine development and control strategies in poultry.

scholarly journals Pseudotyped Bat Coronavirus RaTG13 is efficiently neutralised by convalescent sera from SARS-CoV-2 infected Patients

2021 ◽  
Author(s):  
Diego Cantoni ◽  
Martin Mayora-Neto ◽  
Nazia Thakur ◽  
Ahmed ME Elrefaey ◽  
Joseph Newman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Healthcare Workers ◽  
Immune Escape ◽  
Sequence Similarity ◽  
Single Amino Acid ◽  
Close Relative ◽  
Amino Acid Substitutions ◽  
Vaccination Strategies ◽  
Genome Wide ◽  
Bat Coronavirus

RaTG13 is a close relative of SARS-CoV-2, the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, sharing 96% sequence similarity at the genome-wide level. The spike receptor binding domain (RBD) of RaTG13 contains a large number of amino acid substitutions when compared to SARS-CoV-2, likely impacting affinity for the ACE2 receptor. Antigenic differences between the viruses are less well understood, especially whether RaTG13 spike can be efficiently neutralised by antibodies generated from infection with, or vaccination against, SARS-CoV-2. Using RaTG13 and SARS-CoV-2 pseudotypes we compared neutralisation using convalescent sera from previously infected patients as well as vaccinated healthcare workers. Surprisingly, our results revealed that RaTG13 was more efficiently neutralised than SARS-CoV-2. In addition, neutralisation assays using spike chimeras and mutants harbouring single amino acid substitutions within the RBD demonstrated that both spike proteins can tolerate multiple changes without dramatically reducing how efficiently they are neutralised. Moreover, introducing the 484K mutation into RaTG13 resulted in increased neutralisation, in contrast to the same mutation in SARS-CoV-2 (E484K). This is despite E484K having a well-documented role in immune evasion in variants of concern (VOC) such as B.1.351 (Beta). These results indicate that the immune-escape mutations found in SARS-CoV-2 VOCs might be driven by strong antibody pressures, and that the future spill-over of RaTG13 and/or related sarbecoviruses could be mitigated using current SARS-CoV-2-based vaccination strategies.

Sign in / Sign up

Export Citation Format

Share Document